Abstract
Dual-specificity phosphatases (DUSPs) are a family of protein phosphatases that dephosphorylate both phosphotyrosine and phosphoserine/phosphothreonine residues. DUSPs are de-regulated in many human diseases, including cancers. However, the function of DUSPs in tumorigenesis remains largely unknown. Here, using short hairpin RNA-based gene knockdown, we found that several members of the DUSP family play critical roles in regulating cell proliferation. In particular, we showed that DUSP16 ablation leads to a G1/S transition arrest, reduced incorporation of 5-bromodeoxyuridine, enhanced senescence-associated β-galactosidase activity, and formation of senescence-associated heterochromatic foci. Mechanistically, DUSP16 silencing causes cellular senescence by activating the tumor suppressors p53 and Rb. The phosphatase activity of DUSP16 is necessary for antagonizing cellular senescence. Importantly, the expression levels of DUSP16 are up-regulated in human liver cancers, and are positively correlated with tumor cell proliferation. Taken together, our findings indicate that DUSP16 plays a role in tumorigenesis by protecting cancer cells from senescence.